Abstract 213: Adenosine Signaling in Hypertensive Chronic Renal Disease

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Hypertension is the most prevalent life-threatening disease worldwide and is frequently associated with chronic kidney disease (CKD). However, the molecular basis underlying hypertensive CKD is not fully understood. We sought to identify specific factors and signaling pathways that contribute to hypertensive CKD and thereby exacerbate disease progression. Using high throughput quantitative RT-PCR profiling, we discovered that the expression level of 5’-ectonucleotidase (CD73), a key enzyme that produces extracellular adenosine, was significantly increased in the kidneys of angiotensin II (Ang II)-infused mice, an animal model of hypertensive nephropathy. Using both CD73 and A2B adenosine receptor (ADORA2B)-deficient mice coupled with pharmacological studies, we found that elevated CD73-mediated excess renal adenosine preferentially induced the ADORA2B expression and enhanced kidney ADORA2B signaling contributes to Ang II-induced hypertension. Similarly, in humans, we found that both CD73 and ADORA2B levels were significantly elevated in the kidneys of CKD patients compared to normal individuals and further elevated in hypertensive CKD patients. These findings led us to further discover that elevated renal CD73 contributes to excess adenosine signaling via ADORA2B activation that directly stimulates endothelin-1 (ET-1) production in a hypoxia inducible factor-α (HIF-1α)-dependent manner and underlies the pathogenesis of the disease. Lastly, we revealed that HIF-1α is an important factor responsible for Ang II-induced CD73 and ADORA2B expression at the transcriptional level. Overall, our studies reveal that Ang II-induced renal CD73 promotes the production of renal adenosine that is a prominent driver of hypertensive CKD by enhanced ADORA2B signaling-mediated ET-1 induction in a HIF-1α dependent manner. The inhibition of excess adenosine-mediated ADORA2B signaling represents a novel therapeutic target for the disease.

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